Biomarkers /
KRAS G12D
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Overview
KRAS G12D is present in 4.20% of AACR GENIE cases, with pancreatic adenocarcinoma, colon adenocarcinoma, lung adenocarcinoma, colorectal adenocarcinoma, and rectal adenocarcinoma having the greatest prevalence [4].
Biomarker-Directed Therapies
KRAS G12D is a predictive biomarker for use of afatinib, dacomitinib, erlotinib, gefitinib, osimertinib, cetuximab, and panitumumab in patients.
Of the therapies with KRAS G12D as a predictive biomarker, 2 are FDA-approved and 7 have NCCN guidelines in at least one clinical setting.
Non-small cell lung carcinoma and colorectal carcinoma have the most therapies targeted against KRAS G12D or its related pathways [5].
Afatinib +
Non-Small Cell Lung Carcinoma -
|
Biomarker Criteria:
Sample must match one or more of the following:
|
Predicted Response: Primary Resistance |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: According to NCCN, mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy. |
|
Biomarker Criteria:
Sample must match all of the following:
Sample must match one or more of the following: Sample must match one or more of the following: |
Predicted Response: Primary Resistance |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: According to NCCN, mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy. |
Cetuximab +
Dacomitinib +
Non-Small Cell Lung Carcinoma -
|
Biomarker Criteria:
Sample must match one or more of the following:
|
Predicted Response: Primary Resistance |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: According to NCCN, mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy. |
|
Biomarker Criteria:
Sample must match all of the following:
Sample must match one or more of the following: Sample must match one or more of the following: |
Predicted Response: Primary Resistance |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: According to NCCN, mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy. |
Erlotinib +
Non-Small Cell Lung Carcinoma -
|
Biomarker Criteria:
Sample must match one or more of the following:
|
Predicted Response: Primary Resistance |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: According to NCCN, mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy. |
|
Biomarker Criteria:
Sample must match all of the following:
Sample must match one or more of the following: Sample must match one or more of the following: |
Predicted Response: Primary Resistance |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: According to NCCN, mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy. |
Gefitinib +
Non-Small Cell Lung Carcinoma -
|
Biomarker Criteria:
Sample must match one or more of the following:
|
Predicted Response: Primary Resistance |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: According to NCCN, mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy. |
|
Biomarker Criteria:
Sample must match all of the following:
Sample must match one or more of the following: Sample must match one or more of the following: |
Predicted Response: Primary Resistance |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: According to NCCN, mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy. |
Osimertinib +
Non-Small Cell Lung Carcinoma -
|
Biomarker Criteria:
Sample must match one or more of the following:
|
Predicted Response: Primary Resistance |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: According to NCCN, mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy. |
|
Biomarker Criteria:
Sample must match all of the following:
Sample must match one or more of the following: Sample must match one or more of the following: |
Predicted Response: Primary Resistance |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: According to NCCN, mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy. |
Clinical Trials
KRAS G12D serves as an inclusion eligibility criterion in 9 clinical trials, of which 8 are open and 1 is closed. Of the trials that contain KRAS G12D as an inclusion criterion, 6 are phase 1 (6 open) and 3 are phase 1/phase 2 (2 open).
Trials with KRAS G12D in the inclusion eligibility criteria most commonly target malignant solid tumor, non-small cell lung carcinoma, pancreatic ductal adenocarcinoma, colorectal carcinoma, and malignant colorectal neoplasm [5].
Ipilimumab, nivolumab, bca101, eli-002, and grt-c903 are the most frequent therapies in trials with KRAS G12D as an inclusion criteria [5].
Significance of KRAS G12D in Diseases
Malignant Solid Tumor +
KRAS is altered in 17.89% of malignant solid tumor patients with KRAS G12D present in 4.73% of all malignant solid tumor patients [4].
KRAS G12D is an inclusion criterion in 5 clinical trials for malignant solid tumor, of which 4 are open and 1 is closed. Of the trials that contain KRAS G12D and malignant solid tumor as inclusion criteria, 2 are phase 1 (2 open) and 3 are phase 1/phase 2 (2 open) [5].
Pancreatic Ductal Adenocarcinoma +
KRAS is altered in 80.56% of pancreatic ductal adenocarcinoma patients with KRAS G12D present in 27.78% of all pancreatic ductal adenocarcinoma patients [4].
KRAS G12D is an inclusion criterion in 3 clinical trials for pancreatic ductal adenocarcinoma, of which 3 are open and 0 are closed. Of the trials that contain KRAS G12D and pancreatic ductal adenocarcinoma as inclusion criteria, 2 are phase 1 (2 open) and 1 is phase 1/phase 2 (1 open) [5].
Colorectal Carcinoma +
KRAS is altered in 44.18% of colorectal carcinoma patients with KRAS G12D present in 13.17% of all colorectal carcinoma patients [4].
KRAS G12D is an inclusion criterion in 3 clinical trials for colorectal carcinoma, of which 3 are open and 0 are closed. Of the trials that contain KRAS G12D and colorectal carcinoma as inclusion criteria, 2 are phase 1 (2 open) and 1 is phase 1/phase 2 (1 open) [5].
Pancreatic Carcinoma +
KRAS is altered in 86.36% of pancreatic carcinoma patients with KRAS G12D present in 36.42% of all pancreatic carcinoma patients [4].
KRAS G12D is an inclusion criterion in 2 clinical trials for pancreatic carcinoma, of which 2 are open and 0 are closed. Of the trials that contain KRAS G12D and pancreatic carcinoma as inclusion criteria, 2 are phase 1 (2 open) [5].
Non-Small Cell Lung Carcinoma +
KRAS is altered in 29.61% of non-small cell lung carcinoma patients with KRAS G12D present in 4.26% of all non-small cell lung carcinoma patients [4].
KRAS G12D is an inclusion criterion in 2 clinical trials for non-small cell lung carcinoma, of which 2 are open and 0 are closed. Of the trials that contain KRAS G12D and non-small cell lung carcinoma as inclusion criteria, 1 is phase 1 (1 open) and 1 is phase 1/phase 2 (1 open) [5].
Breast Carcinoma +
KRAS is altered in 1.99% of breast carcinoma patients with KRAS G12D present in 0.13% of all breast carcinoma patients [4].
KRAS G12D is an inclusion criterion in 2 clinical trials for breast carcinoma, of which 2 are open and 0 are closed. Of the trials that contain KRAS G12D and breast carcinoma as inclusion criteria, 2 are phase 1 (2 open) [5].
Pancreatic Adenocarcinoma +
KRAS is altered in 86.35% of pancreatic adenocarcinoma patients with KRAS G12D present in 36.2% of all pancreatic adenocarcinoma patients [4].
KRAS G12D is an inclusion criterion in 1 clinical trial for pancreatic adenocarcinoma, of which 1 is open and 0 are closed. Of the trial that contains KRAS G12D and pancreatic adenocarcinoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Malignant Colorectal Neoplasm +
KRAS is altered in 44.18% of malignant colorectal neoplasm patients with KRAS G12D present in 13.17% of all malignant colorectal neoplasm patients [4].
KRAS G12D is an inclusion criterion in 1 clinical trial for malignant colorectal neoplasm, of which 1 is open and 0 are closed. Of the trial that contains KRAS G12D and malignant colorectal neoplasm as inclusion criteria, 1 is phase 1 (1 open) [5].
Gastric Carcinoma +
KRAS is altered in 13.46% of gastric carcinoma patients with KRAS G12D present in 3.72% of all gastric carcinoma patients [4].
KRAS G12D is an inclusion criterion in 1 clinical trial for gastric carcinoma, of which 1 is open and 0 are closed. Of the trial that contains KRAS G12D and gastric carcinoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Ovarian Carcinoma +
KRAS is altered in 10.16% of ovarian carcinoma patients with KRAS G12D present in 2.94% of all ovarian carcinoma patients [4].
KRAS G12D is an inclusion criterion in 1 clinical trial for ovarian carcinoma, of which 1 is open and 0 are closed. Of the trial that contains KRAS G12D and ovarian carcinoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Hepatocellular Carcinoma +
KRAS is altered in 0.93% of hepatocellular carcinoma patients with KRAS G12D present in 0.46% of all hepatocellular carcinoma patients [4].
KRAS G12D is an inclusion criterion in 1 clinical trial for hepatocellular carcinoma, of which 1 is open and 0 are closed. Of the trial that contains KRAS G12D and hepatocellular carcinoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Head And Neck Squamous Cell Carcinoma +
KRAS is altered in 2.52% of head and neck squamous cell carcinoma patients with KRAS G12D present in 0.31% of all head and neck squamous cell carcinoma patients [4].
KRAS G12D is an inclusion criterion in 1 clinical trial for head and neck squamous cell carcinoma, of which 1 is open and 0 are closed. Of the trial that contains KRAS G12D and head and neck squamous cell carcinoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Squamous Cell Lung Carcinoma +
KRAS is altered in 4.45% of squamous cell lung carcinoma patients with KRAS G12D present in 0.31% of all squamous cell lung carcinoma patients [4].
KRAS G12D is an inclusion criterion in 1 clinical trial for squamous cell lung carcinoma, of which 1 is open and 0 are closed. Of the trial that contains KRAS G12D and squamous cell lung carcinoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Glioblastoma +
KRAS is altered in 1.6% of glioblastoma patients with KRAS G12D present in 0.14% of all glioblastoma patients [4].
KRAS G12D is an inclusion criterion in 1 clinical trial for glioblastoma, of which 1 is open and 0 are closed. Of the trial that contains KRAS G12D and glioblastoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Anal Canal Squamous Cell Carcinoma +
KRAS G12D is an inclusion criterion in 1 clinical trial for anal canal squamous cell carcinoma, of which 1 is open and 0 are closed. Of the trial that contains KRAS G12D and anal canal squamous cell carcinoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Chordoma +
KRAS G12D is an inclusion criterion in 1 clinical trial for chordoma, of which 1 is open and 0 are closed. Of the trial that contains KRAS G12D and chordoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Thyroid Gland Undifferentiated (Anaplastic) Carcinoma +
KRAS is altered in 2.11% of thyroid gland undifferentiated (anaplastic) carcinoma patients [4].
KRAS G12D is an inclusion criterion in 1 clinical trial for thyroid gland undifferentiated (anaplastic) carcinoma, of which 1 is open and 0 are closed. Of the trial that contains KRAS G12D and thyroid gland undifferentiated (anaplastic) carcinoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Uveal Melanoma +
KRAS G12D is an inclusion criterion in 1 clinical trial for uveal melanoma, of which 1 is open and 0 are closed. Of the trial that contains KRAS G12D and uveal melanoma as inclusion criteria, 1 is phase 1 (1 open) [5].
References
1. Hart R and Prlic A. Universal Transcript Archive Repository. Version uta_20180821. San Francisco CA: Github;2015. https://github.com/biocommons/uta
2. The UniProt Consortium. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Research. 2019;47:D506-D515.
3. Liu X, Wu C, Li C, and Boerwinkle E. dbNSFP v3.0: A one-stop database of functional predictions and annotations for human nonsynonymous and splice site SNVs. Human Mutation. 2015;37:235-241.
Liu X, Jian X, and Boerwinkle E. dbNSFP: A lightweight database of human nonsynonymous SNPs and their functional predictions. Human Mutation. 2011;32:894-899.
4. The AACR Project GENIE Consortium. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discovery. 2017;7(8):818-831. Dataset Version 8. This dataset does not represent the totality of the genetic landscape; see paper for more information.
5. All assertions and clinical trial landscape data are curated from primary sources. You can read more about the curation process here.
